8G6I

Coagulation factor VIII bound to a patient-derived anti-C1 domain antibody inhibitor

Summary for 8G6I

• Entry DOI: 10.2210/pdb8g6i/pdb
• EMDB information: 29770
• Descriptor: Coagulation factor VIII chimera from human and pig, NB33 light chain, NB33 heavy chain, ... (4 entities in total)
• Functional Keywords: immune system, blood clotting
• Biological source: Sus scrofa (pig); More
• Total number of polymer chains: 3
• Total formula weight: 215053.95

Authors

Childers, K.C.,Davulcu, O.,Haynes, R.M.,Lollar, P.,Doering, C.B.,Coxon, C.H.,Spiegel, P.C. (deposition date: 2023-02-15, release date: 2023-05-24, Last modification date: 2024-10-30)

Primary citation

Childers, K.C.,Avery, N.G.,Estrada Alamo, K.A.,Davulcu, O.,Haynes, R.M.,Lollar, P.,Doering, C.B.,Coxon, C.H.,Spiegel, P.C.
Structure of coagulation factor VIII bound to a patient-derived anti-C1 domain antibody inhibitor.
Blood, 142:197-201, 2023

PubMed Abstract: The development of pathogenic antibody inhibitors against coagulation factor VIII (FVIII) occurs in ∼30% of patients with congenital hemophilia A receiving FVIII replacement therapy, as well as in all cases of acquired hemophilia A. KM33 is an anti-C1 domain antibody inhibitor previously isolated from a patient with severe hemophilia A. In addition to potently blocking FVIII binding to von Willebrand factor and phospholipid surfaces, KM33 disrupts FVIII binding to lipoprotein receptor-related protein 1 (LRP1), which drives FVIII hepatic clearance and antigen presentation in dendritic cells. Here, we report on the structure of FVIII bound to NB33, a recombinant derivative of KM33, via single-particle cryo-electron microscopy. Structural analysis revealed that the NB33 epitope localizes to the FVIII residues R2090-S2094 and I2158-R2159, which constitute membrane-binding loops in the C1 domain. Further analysis revealed that multiple FVIII lysine and arginine residues, previously shown to mediate binding to LRP1, dock onto an acidic cleft at the NB33 variable domain interface, thus blocking a putative LRP1 binding site. Together, these results demonstrate a novel mechanism of FVIII inhibition by a patient-derived antibody inhibitor and provide structural evidence for engineering FVIII with reduced LRP1-mediated clearance.

PubMed: 37192299
DOI: 10.1182/blood.2023020181

Experimental method

ELECTRON MICROSCOPY (4.23 Å)